Process of producing a brominated lactone useful in the preparation of reserpine and related compounds



United States Patent PROCESS OF PRODUCING A BROMINATED LAC- TONE USEFUL IN THE PREPARATION OF RE- SERPINE AND RELATED COMPOUNDS Robert Joly, Montmorency, and Julien Warnant, Neuilly, France, assignors to Les Laboratoires Frangais de Chimiotherapie, Paris, France, a corporation of France No Drawing. Filed June 16, 1958, Ser. No. 742,045

Claims priority, application France June 17, 1957 3 Claims. (Cl. 260-3433) The present invention relates to a new and improved process of producing a valuable brominated lactone useful in the synthesis of reserpine and related compounds.

Reserpine which corresponds to the following Formula A OCH;

OCH:

is one of the principal constituents of the chalchypines isolated from Rauwolfia heterophylla Roem. et Schult.

It has been described for the first time by R. Paris and R.

Mendoza-Daze, Bulletin des Sciences pharmacologiques, volume 48, page 146 (1941); by R. Mendoza-Daza, doctors thesis of the university (Facult de Pharmacie, Universit de Paris), Paris, 1940; C. Djerassi, M. Gorman, A. L. Nussbaum, J. Reynoso, Journ. Am. Chem. Soc.,

Patented Sept. 6, 1960.

oxo-l,4,4aa,5,8,Saa-heXahydrOnaphthalene-lfl carboxylic acid of Formula I as starting material.

Said starting material is obtained by resolving the corresponding racemic mixture. Resolution of the racemic acid is efiected by preparing the salts of the enantiomorphous isomers of said acid with optically active bases such as quinine, brucine, cinchonine, or the levorotatory ephedrine. The optically ac- I tive salts obtained thereby are isolated and then decomposed to set free the resolved optically active acids.

Thereafter, the resulting dextrorotatory enantiomorphous 5,8-hydroxy-8-oxo-1,4,4aa,5,8,8aa-hexahydronaphthalene-lpwarboxylic acid of Formula I is heated under reflux in methylene chloride with a mixture of sodium com 75, page 5446 1953 vol. 76, page 4463 1954 Reserpine has been isolated in crystalline form by J. M. Muller, E. Schlittler, and H. J. Bein as described in #Experientia, vol. 8, page 338 (1952). Muller et al.

used as starting material the so-called oleoresinsj of Rauwolfia serpentina Benth.

Reserpine has a sedative and a progressively increasing and prolonged hypotensive action. It has also a body temperature reducing efiect and increases intestinal peristalsis. Such properties have made reserpine an adjuvant of the first order in modern therapy and particularly a highly active psychosomatic agent of low toxicity.

It is one object of the present invention to provide a simple and economic synthetic process of preparing reserpine.

Another object of the present invention is to provide a simple and etfective process of preparing the levorotatory lactone of the 6u-bromo-8fi-hydroxy-2a-methoxy- 35,56-epoxy 7 oxo-4aa,8aa-decahydronaphthalene-l/S- carboxylic acid which is useful in the synthetic preparation of reserpine and related compounds.

Other objects of the present invention and advantageous features thereof will become apparent as the description proceeds.

In principle the present invention consists in using the enantiomorphous dextrorotatory isomer of Sp-hydroxy-S- acetate and acetic acid anhydride. The resulting levorotatory lactone of 5,8-hydroxy-8-oxo-l,4,4aa,5,8,8aa-hexahydronaphthalenelfl-carboxylic acid of Formula II is (III) is obtained which is isolated by precipitation with water. Said lactone of Formula III is treated with sodium methylate in methanol so as to convert it into the dextro'rotatory lactone of 8B-hydroxy-2ir-methoxy-L ?,55 epoxy-1,2,3,4,4aa,5,8,8aa-octahydronaphthalene-lfl carboxylic acid which is isolated and subjected to the action of N-bromo succinimide in dilute sulfuric acid. The resulting levorotatory 1,8-lactone of 6a-bromo-7fl,8B-dihydroxy 2oz methoxy-35,5p-epoxy-4aa,8aa-decahydronaphthalene-l/i-carboxylic acid of Formula IV Br i C u H 6C a (v) The isolated lactone is treated with zinc powder in acetone and acetic acid in order to produce the levorota- 1 tory 3;; hydroxy-Za-methoxy-7-oxo-1,2,3,4,4aa,7,8,8aaoctahydronaphthalene-IB-carboxylic acid. The methyl ester of said acid is prepared by reacting the acid with diazomethane in dioxane. The methyl ester is then acetylated by means of acetic acid anhydride in pyridine in order to isolate the levorotatory methyl ester of 3 3- acetoxy-Zu-methoxy-7-oxo-1,2,3,4,4aa,7,8,8aa octahydronaphthalene-lfl-carboxylic acid. Ozone is then reacted with said levorotatory methyl ester in an organic solvent such as acetic acid ethyl ester or methylene chloride at temperatures between 0 C. and --60 C.

The resulting ozonide of Formula VI is converted in lfi-carboxy methyl-Z/S-rnethoxy carbonyl- 3a-methoxy-4fl-acetoxy-6Bformyl cyclohexane. This conversion is eifected by oxidation of the hydrate of 1B- (2',3-dioxopropyl)-2Bmethoxy carbonyl-3a-methoxy-4/3- acetoxy-Gfi-formyl cyclohexane by means of chromic acid or periodic acid. Said compound is obtained by the action of zinc powder on the ozonide of Formula VI in the presence of acetic acid. lfi-carboxymethyl-Z/imethoxy-carbonyl 3u-rnethoxy 4 8-acetoxy GB-formylcyclohexane is more directly obtained by the action of water or of iodic acid or periodic acid on said ozonide. The resulting levorotatory lfi-carboxy methyl-Zfi-metho-xy carbonyl-3a-methoxy-4p-acetoxy-6p-formyl cyclohexane is converted into the methyl ester by means of diazo methane in a mixture of methylene chloride and. ether.

Its methyl ester is then condensed with 6-methoxy tryptamine which condensation product, after a treatment with sodium borohydride and thereafter with alcoholic sodium hydroxide solution, yields the dextrorotatory 1813- hydroxy-l1,17a-dimethoxy-3-oxo-16fi-carboxy-2,3 seco- 20a-yohimbane of Formula VII.

CHs v11 Said compound is converted into the corresponding lactone of Formula VIII.

i 0 (VIII Ring closure of said lactone to the lactone of 18fi-hydroxy 11,1704- dimethoxy-l6fl-carboxy-3,4-dehydro-20ayohimbane of Formula IX is achieved by reaction with phosphorus oxychloride while heating.

Said lactone of Formula IX is reduced by means of zinc powder in the presence of acetic acid to the lactone of reserpic acid or by the action of a double hydride to the lactone of isoreserpic acid which according to processes known to the art is isomerized to the lactone of reserpicacid of Formula X.

Reserpic acid lactone is then converted according to known methods into the methyl ester of reserpic acid and said methyl ester is subjected to the action of 3,4,5-trimethoxy benzoylchloride, thereby yielding reserpine.

The present invention is especially concerned with the step of oxidizing the levorotatory 1,8-lactone of 6a-bromo-7/3,8B-dihydroxy 2a methoxy-3/3,5B-epoxy- 4am,Saa-decahydronaphthalene-l 8-carboxylic acid of Formula IV into the levorotatory lactone of 6:xbromo-8B- hydroxy-Za-methoxy-SB,SIB-epoxy 7 oxo-4aa,8aa-decahydronaphthalene-lfi-carboxylic acid of Formula V.

' This oxidation is carried out by means of chromic acid in the presence of phosphoric acid in a Water-immiscible solvent which is not affected by chromic acid, such as a lower alkyl halogenide, for instance, dichloro ethane, tetrachloro ethane, methylene chloride, and the like. By the use of phosphoric acid as a catalyst in this step of the process of producing reserpine the yield of the levorotatorylactone of 6a-bromo-8B-hydroxy-2amethoxy-Bfififi-epoxy 7 oxo-4aa,8aa-decahydronaphthalene-lfl-carboxylic acid is considerably increased from about 74%, obtained when working in the absence of phosphoric acid, to 909l% of the theoretical amount. As this step is one of the initial steps in the many steps required for preparing reserpine and related compounds, such an unexpected increase in the yield of said intermediate is of considerable importance with regard to the industrial efiiciency of the process of producing reserpine and related compounds synthetically.

- Oxidation is carried out at room temperature, preferably by introducing the oxidizing agent consisting of a solution of the theoretical amount of chromic acid and of phosphoric acid in aqueous acetic acid in several portions. As soon as the oxidation is completed, the organic solvent layer is removed by decanting, washed with water, and evaporated to dryness. The acid of Formula V is purified by recrystallization from an organic solvent.

The following examples serve to illustrate the present invention without, however, limiting the same thereto. More particularly, the nature of the solvents and reactants used, the order of introducing said reactants into the reaction mixture, the reaction temperature and duration, and .the like may be varied in accordance with the principles set forth herein and in the claims annexed hereto. In said examples the yield is calculated without taking into consideration the mother liquors which still contain a considerable amount of the desired reaction products.

The melting points given in the examples are points of instantaneous melting determined on the Maquenne block. The rotatory powers have been measured in ethanol solution.

EXAMPLE 1 Resolution of dl-I;3-carboxy-5p-hydroxy-8-keto l,4,4au,5, 8,8aa-hexahydr0naphthalene by means of quinine and isolation of lJfi-carb0xy-5/3-hydroxy-8-keto-1,4,4aa,5, 8,8aa-hexahydronaphthalene (Formula I 104 g. of dl-1,8-carboxy-Sfi-hydroxy-S-keto-l,4,4a x,5, 8,8aot-hexahydronaphthalene of Formula I, prepared as described by Woodward et al. in Journ. Am. Chem. Soc., vol. 78, page 2023 (1956), are heated under reflux in 400 cc. of ethanol until complete solution is achieved. 162 g. of quinine free of water of crystallization is added at once to the boiling liquid. The salt of quinine with the levoro-tatory enantiornorphous compound crystallizes soon thereafter. Boiling without agitation is continued for 15 minutes. The mixture is then placed in ice for two hours and the crystals are filtered oil. The filtered crystals are twice made into a paste, each time with 100 cc. of ice-cold ethanol. The pasted crystals are again filtered and the salt of quinine with the 'levorotatory enantiomorphous compound is dried. The

6 yield amounts to 117 g. The melting point is 225 C.'; rotatory power [a] =151i4.

The resulting product is suspended in 300 cc. of water and 500 cc. of chloroform. 30 g. of sodium bicarbonate are added thereto and the mixture is stirred for three hours until evolution of carbon dioxide ceases. The resulting emulsion is allowed to settle. The chloroform layer is separated from the aqueous layer and is washed several times with a saturated aqueous solution of sodium bicarbonate. The aqueous layer is extracted three times with chloroform in order to remove therefrom the quinine which may be contained therein. The aqueous layer is combined with the bicarbonate wash waters of the chloroform layer and the combined aqueous solutions are acidified by the addition of 5 N hydrochloric acid to a pH of 2.0. The acidified solution is saturated with sodium chloride and is allowed to stand for one hour. The precipitate is filtered and dried in a vacuum above solid sodium hydroxide at 20 C. .33 g. of the levorotatory compound of Formula I are obtained. The melting point is 210 C.; the rotatory power [a] =-78 :4". The crude product contains about 3 g. of sodium chloride. On recrystallization from a mixture of equal parts of alcohol and ether the pure levorotatory enantiomorphous compound is obtained. Its melting point is 210 0.; its optical rotation [a] =-85 (concentration: 0.5% in ethanol).

Analysis (C H O =208.2l).Calculated: 63.45% C, 5.81% H, 30.74% 0. Found: 63.3% C, 5.8% H, 30.5% 0.

The aqueous mother liquors remaining after removing the crude product are extracted several times with a mixture of chloroform and ethanol (3:1). The combined extracts are washed with salt-containing water until their pH is 4.0. The washed extracts are then dried over magnesium sulfate and evaporated to dryness in a vacuum. A second batch of the levorotatory enantiomorphous compound is recovered showing a rotatory power [a] =84 after it has been made into a paste by means of a mixture of chloroform and ethanol (3:1). The yield is 3 g.

The mother liquor from the paste of crystals is also evaporated to dryness and the residue is triturated with chloroform. Thereby a third batch of the crystalline enantiomorphous compound is obtained. The total resolllltion yield, thus, amounts to 80% of the theoretical yie d.

EXAMPLE 2 Isolation of d-J,B-carb0xy-5B-hydr0xy-8-ket0-1,4,4aoc, 5,8,8aa-hexahydrona'phthalene The ethanolic mother liquors obtained according to Example 1 after removing the crystals of the quinine salt of the levorotatory isomer of Formula I are evaporated to dryness. The amorphous residue consists of a mixture of the quinine salt of the dextrorotatory enantiomorphous compound and about 10% of the quinihe salt of the levorotatory enantiomorphous compound. Said residue is suspended in a mixture of 300 cc. of Water and 500 cc. of chloroform with agitation, as described in Example 1. 30 g. of sodium bicarbonate are added thereto. Decomposition of the quinine salt is completed after about 1 hour. The resulting emulsion is allowed to settle. The chloroform layer is removed and washed twice with an aqueous solution of sodium bicarbonate. The aqueous layer is extracted several times with chloroform in order to completely remove the quinine contained therein. The combined aqueous sodium bicarbonate solutions are acidified by the addition of 5 N hydrochloric acid to a pH of 2.0. The acidified solution is allowed to crystallize. The crystals are filtered ofii after about 1 hour and are dried. 21 g. of a mixture of the racemic compound of Formula I with a small amount of the dextrorotatory enantiomo-rphous compound are obtained thereby. The optical rota tion of :said mixture is [a] 22 (concentration: 0.5% in ethanol).

' fIhe filtrate remaining after filtering ofi said mixture of racemate and dextrorotatory compound is saturated with sodium chloride and is extracted several times with a mixture of chloroform and ethanol (3:1). The resulting extract in the organic solvent is washed with saltcontaining water until its pH is 4.0, dried over magnesium sulfate, and evaporated to dryness in a vacuum. The residue is made into a paste by means of chloroform and yields a first batch of crystals in the amount of 16 g. This product, which represents the pure dextrorotatory enantiomorphous compound of Formula I has a melting point of 210 C. and an optical rotation The mother liquors yield after evaporation and allowing to stand for several days a second batch of crystals.

The mixture of racemic compound and dextrorotatory enantiomorphous compound in the amount of 21 g. (optical rotation [u] =H22) obtained as described hereinabove is dissolved in as small an amount of warm water as possible, usually about 4 parts by volume. The solution is cooled with ice and the precipitate is filtered off. 11 g. of the racem-ic compound having a melting point of 202 C. are recovered. They are returned to the resolving process.

The mother liquors obtained thereby are saturated with sodium chloride and yield, by proceeding in the same manner as described hereinabove, a further amount of dextrorotatory enantiomorphous compound.

EXAMPLE 3 Resolution of dl-lB-carboxy-fifl-hydrxy-8-ket0-1,4,4aa, 5,8,Sua-hexahydronaphthalene by means of brucme The procedure is the same as described hereinabove in Examples 1 and 2, whereby, however, 1 mol of brucine is used for 1 mol of the racemic compound. The brucine salt of the levorotatory isomer is obtained in a yield of 88% of the theoretical yield. Its melting point is 210 C., its rotatory power [a] =-4O (concentration: 0.5% in ethanol). Said brucine salt is decomposed as described hereinabove in Example 1 and yields the levorotatory enantiomorphous compound of the rotatory power [a] =85. The mother liquors of the brucine salt of the levorotatory enantiomorphous compound yield, when treated according to the process described in Example 2, the dextrorotatory enantiomorphous compound.

EXAMPLE 4 Preparation 0 the cinchonine salt of the dextrorotatory Ifi carboxy-Sfi hydroxy 8 keto 1,4,4aa,5,8,8aochexahydronaphthalene in water 1 g. of dl-lfl-carboxy-Sfl-hydroxy-S-keto 1,4,4aa,5,8, Baa-hexahydronaphthalene is dissolved in 10 cc. of water of a temperature of 95 C. 1.4 g. of cinchonine are added to said solution. The mixture is stirred at 90 C. for 5 minutes and is cooled with ice. The precipitated crystals are filtered oif, washed with water and dried in a drying oven at 80 C. 940 mg. of the cinchonine salt of the dextrorotatory lfi-carboxy-5fl-hydroxy-8-keto-1,4,4aa,5,8,8aahexahydronaphthalene are obtained thereby. The yield is 78% of the theoretical yield. The compound is obtained in the form of fine, colorless platelets. The melting point is about 192 0., its optical rotation [a] =I+146:6 (concentration: 0.5% in ethanol). The salt is soluble in ethanol, methanol, acetone; insoluble in ether and petroleum ether; and slightly soluble in water.

Analysis (C H O N =502.59).--Calculated: 71.69% C, 6.82% H, 5.57% N. Found: 71.4% C, 6.8% H, 5.4%.N.

8 EXAMPLE 5 Preparation of the dextrorotatory cinchonine salt of 1B- carboxy 5B hydroxy 8-keto 1,4,4aa,5,8,8aa-hexahydronaphthalene in aqueous ethanol ,and dried in a drying oven at C. In this manner 1g. of the cinchonine salt of dextrorotatory 1 3-carboxy- SB-hydroxy-S-keto-1,4,4a x,5, 8,'8awwhexahydronaphthalene is obtained which is similar in all respects to the compound obtained according to Example-4. The yield is 84% of the theoretical yield.

EXAMPLE 6 Decomposition of the cinchonine salt of dextrorotatory 15 carboxy 5 B hydroxy8-keto-1,4,4aa,5,8,8aa-hexahydronaphthalene 940 mg. of the cinchonine salt of dextrorotatory 1B- carboxy-SB-hydroxy 8 keto l,4,4ao,5,8,8aa-hexahydronaphthalene obtained according to Example 4 or 5 are suspended in 4 cc. of water. 1 cc. of 20% ammonia solution is added thereto. The mixture is stirred. The precipitated cinchonine is filtered off and is washed with water. On drying 0.5 g. thereof are recovered. The

recovery yield is The remaining solution is acidified by the addition of concentrated hydrochloric acid (22 B.) to a pH of 1.0. The acidified solution is concentrated in a vacuum to a volume of 2 cc. and is saturated with sodium chloride. The precipitate is filtered ofi, redissolved in 10 cc. of acetone and filtered. 20 cc. of ether are added to the acetone solution which is then concentrated to a volume of 3 cc. The resulting crystals are filtered off and dried. '330 mg. of pure dextrorotatory 1B-carboxy-5/8-hydroxy-8-keto-1,4, 4aa,5,8,8aa -hexahydronaphthalene are obtained. 'The yield is 66% of the theoretical yield. Said dextrorotatory compound melts instantaneously at 210 C. with decomposition. Its optical rotation is [cc] =+83i4 (concentration: 0.5% in ethanol). It is in all its characteristic properties identical with a product obtained according to Example 2.

EXAMPLE 7 Preparation of the ephedrine salt of the dextrorotatory 1,8 carboxy 5 ,B hydroxy-8-ket0-1,4,4aa,5,8,8aa-hexahydronaphthalene g. of 1 S-carboxy-Sfi-hydroxy-S-keto-1,4,4aa,5,8,8auhexahydronaphthalene are dissolved in 500 cc. of absolute ethanol while boiling. The solution is cooled to 50 C. 108 cc. of a water-free solution of 71.5% of levo-ephedrine in ethanol are added thereto rapidly. The resulting mixture is cooled to 5 C. and is allowed to stand at said temperature for 2 hours. The precipitated crystals are filtered oil and dried in a vacuum. 67.5 g. of the ephedrine salt of the dextrorotatory 1fi-carboxy-SB-hydroxy-8-keto-1,4, 4am, 5,8,8aa-hexahydronaphthalene of the melting point 153 C. and the optical rotation [a] =+3O :1" (concentration: 5% in water) are obtained. The yield is 75% of thetheo-retical yield. The resulting product is obtained in the form of fine colorless needles.

EXAMPLE 8 Decomposition of the ephedrine salt of the dextrorotatory 1B carhoxy 5 B hydroxy-8-ket0-1,4,4aa,5,8,8aor-hexa hydronaphthalene 67.5 g. of the ephedrine salt of the dextrorotatory 1B- carboxy-Sfi-hydroxy 8 keto 1,4,4aa,5,8,8aa-hexahydronaphthalene obtained according to Example 7 are suspended in 250 cc. of acetone. 16 cc. of concentrated 9. hydrochloric acid are added thereto at 20 C. while stirring. The mixture is stirred at room temperature for 15 minutes. The hydrochloride of levo-ephedrine set free thereby is filtered 011?. The filtrate is evaporated to dryness in a vacuum. The resulting residue is made into the paste 5 times with water, each time with 10 cc. of water, and is dried in a vacuum at 80 C. 34.4 g. of pure dextrorotatory I/S-carboxy-Sfi-hydroxy 8 keto 1,4, 4aa,5,8,8aa-hexahydronaphthalene are obtained. The yield is 92% of the theoretical yield. The compound melts instantaneously at 210 C. with decomposition. Its optical rotation is [a] +83:4 (concentration: 0.5% in ethanol). It is in all its properties identical with the product obtained according to Example 2.

EXAMPLE 9 Preparation of the levorotatory lactone of 5 8-hydroxy- 8-0x0-1,4,4aa,5,8,8aa-hexahydronaphthalene- 113 carboxylic acid (Formula II) 8 g. of the dextrorot-atory SB-hydroxy-S-oxo-l,4,4aa,5, 8,8aa-hexahydronaphthalene-lfi-carboxylic acid prepared according to Example 6 and 4 g. of pulverized sodium acetate are introduced into a mixture of 200 cc. of methylene chloride and 16 cc. of acetic acid anhydride. The mixture is heated under reflux for 2 hours and is then cooled. 16 cc. of pyridine and 16 cc. of methanol are added thereto. The resulting mixture is allowed to stand at room temperature for one hour and is acidified by the addition of 2 N hydrochloric acid to a pH of 1.0. The solvent layer is separated, washed with water and sodium bicarbonate solution, dried over magnesium sulfiate, and evaporated to dryness in a vacuum. The residue is dissolved in 30 cc. of ether, heated under reflux, and cooled with ice. The precipitate is filtered off and is washed with ether. 6.1 g. of the levorotatory lactone of Sfl-hydroxy- 8 oxo 1,4,4au,5,8,8aa hexahydronaphthalene 1e carboxylic acid of Formula II are obtained. The yield is 83% of the theoretical yield. The melting point is 108 C. The optical rotation is [al =-790i20 (concentration: 0.5% in ethanol). The compound is obtained in the form of colorless crystals which are soluble in acetone and chloroform and very little soluble in ether.

Analysis (C H O =190.19).-Calculated: 69.46% C, 5.30% H, 25.24% 0. Found: 68.8 C, 5.6% H, 24.8% 0.

EXAMPLE 10 Preparation of the dextrorotatory lactone of 8,8-hydrxy- 2ix-br0m0-3B,5fl-ep0xy 1,2,3,4,4au,5,8,8aa-0ctahydronaphthalene-1 B-carboxylic acid (Formula III) (a) PREPARATION OF THE LEVOROTATORY 1,8LAC- TONE OF B,8B-DIHYDROXY 1,4aa,'5,8,8'aa HEXAHY- DRONAPH'IHALENE-lfi-CARBOXYLIC ACID 40 g. of molten aluminum isopropylate and 500 cc. of

anhydrous isopropanol are mixed. A few drops of the mixture are distilled ofi and 20 g. of the levorotatory lactone of SB-hydroxy-S-oxo-l,4,4aa,5,8,8aa-hexahydronaphthalene-IB-carboxylic acid of Formula II, prepared according to Example 9, are added thereto. The reaction mixture is concentrated by distillation to a volume of 100 cc. and is cooled. 300 cc. of methylene chloride are added thereto. The solution is washed with N sulfuric acid and with Water, dried over magnesium sulfate, and evaporated to dryness. The residue is dissolved in 50 cc. of ice-cold ether. The precipitated crystals are filtered oil. 17.1 g. of the levorotatory 1,8-lactone of 5;3,8,8-dihydroxy-l,4,4au,5,8,8aa-hexahydronaphthalene-1fl carboxylic acid are obtained thereby. The yield is about 85% of the theoretical yield. Its melting point is 151 C.; its optical rotation is [a] -'=3 (concentration: 0.5 in ethanol). The product, which heretofore has not been described, is obtained in the form of colorless crystals which are soluble in ethanol and chloroformandvery little soluble in ether.

1O Analysis (Gi l-T 0 192.21 .--Calculated: 68.73 C, 6.29% H, 24.97% 0. Found: 68.8% C, 6.1 H, 25.2% 0.

(b) PREPARATION OF THE DEXTRORO'IATORY LAC- 411,5,8,8aa-0CTAHYDRONAPHTHALENE 1B 'CARBOX- YLIC ACID (FORMULA III) 11.5 g. of the levorotatory 1,8-lactone of 55,8,B-dihydroxy-1,4,4aa,5,8,8aa-hexahydronaphthalene-IB-carboxylic acid prepared according to Example 10aare introduced into 55 cc. of tertiary butanol. The mixture is stirred at 25 C. for 5 minutes. 10.8 g. of N-bromosuccinimide are added thereto in small portions while stirring is continued. The mixture is stirred for 15 minutes, 110 cc. of water are added thereto drop by drop, and stirring is continued for 15 more minutes. The precipitate is filtered ofi, Washed with 20 cc. of Water, and dried at 70 C. in an oven. Thereby 13.7 g. of the dextrorotatory lactone of 8fl-hydroxy-2a-bromo-35,55-epoxy-1,2,3, 4,4au,5,8,8au-octahydronaphthalene-lfl-carboxylic acid of Formula HI are obtained. The yield is of the theoretical yield. The melting point of said acid is 152 C.; its optical rotation is [a] ==;+93 (concentration: 0.5 in ethanol). The new product is obtained in the form of colorless crystals which are soluble in acetone and chloroform but very little soluble in ether.

Analysis (C H O' Br=271.12). Calculatedz 48.73% C, 4.09% H, 17.70% 0, 29.48% Br. Found: 48.7% C 4.3% H, 17.8% 0, 29.6% Br.

EXAMPLE 11 Preparation of 18B-hydr0xy-1L1 7a-dimeth0xy-3-0x0-1 6,3- carb0xy-2,3-sec0-20a-y0himbane (Formula VII) (0) PREPARATION OF THE DEXT 11 g. of the dextrorotatory lactone of Sfl-hydroxy-Zabromo-3B,5,B-epoxy 1,2,3,4,4aa,5,8,8a z octahydronaphthalene-lfl-carboxylic acid of Formula III, prepared according to Example 10b, are made into a paste by mixing with 25 cc. of methanol. The paste is diluted with 55 cc. of methanol. 19.9 cc. of a solution of 5 g. of sodium metal in cc. of methanol are then added thereto. The reaction mixture is allowed to stand at a temperature of 20 C. for three hours. Ten drops of glacial acetic acid are added thereto and the mixture is evaporated to dry ness in a vacuum. The residue is dissolved in 1000 cc. of ether. The solution is filtered, concentrated by evaporation to a volume of 50 cc., and cooled with ice. The precipitated crystals are filtered 01f. 8.38 g. of the dextrorotatory lactone of 8fi-hydroxy-2oc-methoxy-3fi,5fl-epoxy- 1,2,3,4,4a x,5,8,8aa-octahydronaphthalene 1/3 carboxylic acid are obtained. Melting point: 102'C.; optical rotation [al =-+48i3 (concentration: 0.5% in ethanol). The yield is 92% of the theoretical yield. The new compound is obtained in the form of colorless crystals which are soluble in acetone and chloroform and very slightly soluble in ether.

Analysis (C H O =222.23).--Calculated: 64.85% C, 6.35% H, 28.80% 0. Found: 64.8% C, 6.5% H, 28.3% 0.

'(b) PREPARATION OF THE unvono'mruonx 1,8-LAC- OF 6a-BROMO-7B,SIS-DIHYDROXY-Za-METHOXY- '3B,0B-EPOXY-4a.a,8aa DEYOAHYDRONAPHTHAIJENEJB- CARBOXYLIC ACID (FORMULA IV) 8.38 g. of the dextrorotatory lactone of 8,6-l1YtlIOXY-2amethoxy-3,6,5[3-epoxy-1,2,3,4,4aa,5,8,8aa octahydronaphthalene-lfi-carboxylic acid obtained according to Example 11a are introduced into 75 cc. of water. 15 cc. of N sulfuric acid and then 7.55 g. of N-brorno succinimide are added thereto. The reaction mixture is heated to 50 C. for about 30 minutes. After cooling, the precipitate is filtered off and dried in a vacuum. Thereby, 9.25 g. of the levorotatory 1,8-lactone of 6a-bromo-7fi,8/3-dihydroxy 20c methoxy 35,5,5 epoxy 4arx,8a decahydronaphthalene-lfi-carboxylicacid are obtained' They'ield is 79% of the theoretical yield. The melting point of the compound is 203 C., its optical rotation is ('0) PREPARATION OF THE IJEVOR'OTATiORY LACTONE OF 641. BROMO 8B HYDROXY 2a METHOXY 35,55- EPOXY-7-OXO 4aa,8aa DECAHYDRONAPHTHALENE- IlB-CARBOXYL'IC A'CID (FORMIULA V) 8.48 g. of the levorotatory 1,8-lactone of 6a-bromo-7fl, 8fl-dihydroxy-2a-methoxy 3fi,5,8-epoxy-4aa,Saa-decahydronaphthalene-lfi-carboxylic acid obtained according to Example 111) are added to 25 cc. of acetic acid. 31 cc. of a solution of 11.3% of chromic acid in acetic acid are added to said mixture drop by drop without agitation. The temperature during said addition is maintained between about C. and +10 C. The mixture is allowed to stand at room temperature for 3 hours and is stirred thereby from time to time. 12 cc. of methanol are added thereto. The mixture is stirred for one hour. 50 cc. of water are then added, and the reaction mixture is extracted three times with chloroform. The extracts are combined, washed with water, dried over magnesium sulfate, and evaporated to dryness in a vacuum. The residue is dissolved with ether, filtered, and dried. 8.2 g. of the levorotatory lactone of 6oi-bromo-8fl-hydroxy-2amethoxy-3fl,5/3-epoxy 7 oxo 4aot,8aa-decahydronaphthalene-lfi-carboxylic acid are obtained. The yield is 74% of the theoretical yield. The melting point of said compound is 152 C.; its optic-a1 rotation is (concentration: 0.5% in ethanol). The resulting prodnot which has not been described heretofore is obtained in the form of colorless crystals which are soluble in acetone and chloroform and are almost insoluble in ether.

Analysis (C H O Br=317.14).-Calculated: 45.44% C, 4.13% H, 25.22% 0, 25.20% Br. Found: 45.9% C, 4.2% H, 25.5% 0, 24.8% Br.

The same compound is obtained in a much higher yield when proceeding according to the present invention as follows:

w 1 kg. of the levorotatory 1,8-lactone of 6m-brom0-7B, '8j3-dihydroxy-2 t-methoxy 313,55 6POXy-480t,8a0t-dCahY- dronaph'thalene-1,8-carboxylic acid of Formula IV obtained according to Example 11b and 2.5 l. of acetic acid are added to 15 l. of dichloroe'thane while stirring mechanically. To the resulting suspension there are added, while stirring vigorously, 1.5 l. of an oxidizing mixture prepared by dissolving 7 00 g. of chromic acid in 700 cc. of water and adding thereto 620 cc. of phosphoric acid of 55 B. (density: 1.61) and 1,200 cc. of pure acetic acid while cooling from the outside. Thereby, the temperature is maintained at C. After addition is completed, stirring is continued at 1820 C. for 30 more minutes. The starting material'di'ssolves and a greenish emulsion is formed. 500 'cc. of the oxidizing mixture described above are added at once to said emulsion. Stirring is continued at the same temperature for /z hour. This operation is repeated twice, thereby adding the remainder of the oxidizing mixture. The reaction mixture is allowed to stand and to separate into two layers which are separated by means of a separating funnel. The dichloro ethane layer is washed several times with 'Water and the wash waters are extracted several times with dichloro ethane. The resulting dichloro ethane extracts are combined; 'washed with water, and mixed with the initially obtained dichloro ethane solution. The combinedextracts are dried over magnesium sulfate, filtered,iand evaporated to dryness in a vacuum. The resulting residue which is the desired compound of Formula V is taken up in ethyl acetate and the solution is distilled to remove entrained dichloro ethane. The residue is'again taken up in half of its volume of ethyl acetate. .On crystallization at a low temperature, filtration with suction, washing with ethyl acetate cooled to 10 C. to -15 C., and drying, 900 g. of the levorotatory lactone of "6a bromo 8,6 hydroxy-2a-methoxy-3 8,5,8- epoxy 7 oxo 48.x,8aoc decohydronaphthalene-lfi-carboxylic acid of Formula V are obtained. The compound melts at 151-1:52 C. and has a specific rotatory power of [a] =245 to -255 (concentration: 1% in tetrahydrofuran) (d PREPARATION on THE IAEVOROTATORY arr-HY- DROXY 2a. METHOXY 7 0X0 1,2,3,4,4aa,7,8,8aa- 'O'CTA'HYDRONAPHTHALENE-lB CARB'OXYLIC .ACID

3.88 .g. of the levorotatory lactone of Goa-brOHLO-8B- hYdIOXY-ZOL-IIIC'EIIOXY "3,8,55 epoxy-7-oxo-4aa,Saw-decahydronaphthalene-lfi-carboxylic acid obtained according to Example 11c are dissolved in a mixture of 70 cc. of acetone and 8 cc. of acetic acid. The solution is cooled to a temperature of about 5 C. and 15.5 g. of zinc powder are added thereto. The mixture is stirred for several minutes whereby the temperature is maintained at +15 C., filtered, and the filtrate is evaporated to dryness in a vacuum. The residue is dissolved in chloroform containing 20% of ethanol. '8 cc. of water are added thereto. The mixture is acidified by the addition of 7 N sulfuric acid to a pH of 1.0 and is extracted with chloroform containing 20% of ethanol. The chloroform extracts are combined, dried over magnesium sulfate, and evaporated to dryness in a vacuum. The residue is dissolved in a mixture of acetone and ether (2:3). On cooling with ice, crystals are obtained which are filtered off and dried at C. The levorotatory 3/3-hydroxy 2a-methoxy-I7- oxo 1,2,3,4,4aa,7,8,8aa octahydronaphthalene-lfl-carboxylic acid is obtained thereby in a yield of about 82%. The melting point of said acid is 197 C.; its optical rotation is [a] =-170:5 (concentration: 0.5 in ethanol). The new compound is obtained in the form of small colorless prismatic crystals which are soluble in water, alcohol, and acetone, but very little soluble in ether, and insoluble in chloroform.

Analysis (C H C =240.25). Calculated: 59.99% C, 6.71% H, 33.30% 0. Found: 60.2% C, 6.7% H, 33.7% 0.

-(e) PREPARATION OF THE LEVOROTATORY METHYL ESTER OF 3fl-HYDROXY-2a-METHOXY-7-OXO-1,2,3 4, igt5OCfliAHYDRONAPHTHALENE 1B 'CARBOX- 4.2 g. of 3,8-hydroxy-2a-methoxy-7-oxo-1,2,3,4,4aa,7,8, 8'aa-octahydronaphthalate-lfi-carboxylic acid obtained according to Example 11d are dissolved in 160 cc. of dioxane while heating. The solution is cooled to 10 C. A solution of 'di'azomethane in methylene chloride is added thereto until the col-or of the solution remains yellow. The mixture is allowed to stand at room temperature for 5 minutes and is'then evaporated to dryness in a vacuum. 50 cc. of ether are added to the residue whereby crystallization takes :place. After filtering and drying the crystals, the levorotatory methyl ester of Bfi-hYGIOXY-Zotmethoxy 7 oxo-1,2,3,4,4aa,7,8,8aa-octahydronaphthalene-lfl-carboxylic acid is obtained with a yield of Said ester'is obtained in the form of small colorless crystals which are soluble in alcohol, acetone, and chloroform, but are almost, insoluble in ether. Its melting point is 166 C.; its optical rotation is [a] =170i5 (concentration: 0.5% in ethanol).

Analysis (C H O =254.27).-Calculated: 61.40% C, 7.14% H, 31.46% 0. Found: 61.4% C, 7.1% H, 31.7% 0.

(7') PREPARATION OF THE LEVOROTATIORY Mill THYL ESTER OF 3B-ACETOXY-2a-MIETHOXY-7-OXO-1,2,3,4,4aa,

7,8,8aa. OCTAHYDRONAPHTHALENE 1B *CLARBOX- 'YLIC ACID 1 3.2 g. of the levorotatory methyl ester of 3 3-hydroxy- 2u-rnethoxy-7-oxo-1,2,3,4,4aa,7,8,8aa octahydronaphthalene-lB-carboxylic acid obtained according to Example 10e are introduced into 12 cc. of pyridine. 10 cc. of acetic acid anhydride are added thereto. The mixture is allowed to stand. at room temperature overnight. Water is added thereto. and the mixture is extracted with chloroform. Thechloroform extracts are washed with 2 N hydrochloric acid, salt-containing water, and sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to dryness in a vacuum. The residue is dissolved in ether. Di-isopropyl ether is added to the ethereal solution until the resulting turbidity persists. The precipitated levorotatory methyl ester of 3B-acetoxy-2a-methoxy-7-oxol',2,3,4,4aa,7,8,8aa octahydronaphthalene 1 fi-carboxylic acid is filtered off. Its melting point is 96 C. its optical rotation is [a] =-206i5 (concentration: 0.5% in ethanol). The yield is 90% of the theoretical yield. The new compound is obtained in the form of colorless crystals which are soluble in alcohol, acetone, and chloroform and are only slightly soluble in ether.

' Analysis (C H O =296.31).-Calculated: 60.80% C, 6.80% H, 32.40% 0. Found: 60.7% C, 6.8% H, 32.6% 0.

( Q YPREPARATION OF DEVOROTATORY lfi-CARBOXY- METHYL 2B METHOXY CARBONYL-{Sa-METHOXY- 4B-ACETOXY-6B-FORMYL CYCLOEEXANE IN ONE RE- uc'rroN STEP 200 mg. of the levorotatory methyl ester of 3fi-acetoxy-. 2a methoxy-7-oxo-1,2,3,4,4a11,7,8,8aa-octahydronaphthalene-lfi-carboxylic acid obtained as described in Example 11] are dissolved in cc. of water-free acetic acid ethyl ester. After cooling, the mixture is ozonized at a temperature of --30 C. by allowing an ozonized oxygen current with'an ozone content of 1% to pass through the solution at a rate of 0.2 l./min. for 1 /2 hours. As much of the dissolved ozone as possible is then removed from the solution by passing therethrough a current of nitrogen for about 5 minutes. The temperature of the solution is allowed to increase to room temperature. 2 cc. of water are added. The mixture is stirred for about minutes and its acid component is extracted by stirring with a saturated aqueous solution of sodium bicarbonate. The aqueous layer is separated, acidified to a pH of 1.0, saturated with sodium chloride, an extracted with methylene chloride. The extract is evaporated to dryness after drying over magnesium sulfate. 128 mg. of the desired levorotatory aldehyde are obtained. The yield is about 60%. After trituration with a small amount of ether the aldehyde has a melting point of 165 C. Its optical rotationis [al =27:2 (concentration: 0.5% in ethanol).

When applying the same process steps to the correspondingracemic compound or to the dextrorotatory isomer there are obtained the respective racemic compound orthe' dextrorotatory isomer which has an optical rotation [a] =+26 (concentration: 0.5 in ethanol). The yields are about the same as those of the levorotatory aldehyde.

(h) PREPARATION OF THE LEVOROIATORY METHYL ESTER 0F IB CARBOXY METHYL-QB-METHOXY CAR- BONYL 3:: METHOXY 45 ACETOXY 6B FORMYL CY'CLOHEXANE 450 mg. of the levorotatory IB-carboxy methyl-2B- methoxy carboxyl-3a-methoxy-4 fi-acetoxy-6fl-formyl cyclohexane obtained according to the Example 77g are suspended at 0 C. in 15 cc. of ether. A solution of diazomethane in methylene chloride is added thereto until the color of the solution remains yellow. The reaction mixture is allowed to stand at 0 C. for five minutes and is then evaporated to dryness in a vacuum. The resulting residue forms a colorless gum which can directly be subjected to the following reaction steps:

('1') PREPARATION OF THE COND'ENSATION PRODUCT OF THE LEVOROTATORY METHYL ESTER 0F 1fiCAB.- BOXY METHYL 2B METHOXY CARBONYL-BaJVIETH- XY-iB-ACETOXY-GB-FORMYL CYC'LOHEXANE WITH G-MIEHTHOXY TRYPTAMINE The colorless gum obtained according to Example 11h:

is dissolved in 3 cc. of benzene. A lukewarm solution of 284 mg. of 6-methoxy tryptamine in 18 cc. of benzene is (j) PREPARATION OF DEXTROROTATORY ilSfi-ACET- OXY 11 17a. DIMETHOXY 3 OXOE- 1 6B METHOXY CARBONYL-2,3-SECO-20a-YO AN The colorless gum obtained according to Examples 11g, 11h, and 111 bystarting with 1.408 g. of the levorotatorymethyl ester of 3B-acetoxy-2a-methoxy-7-oxo-l,2,3,4,4aa, 7,8,8aa-octahydronaphthalene-1[i-carboxylic acid is dissolved in 47 cc. of methanol. 1.250 g. of sodium borohydride are added thereto. The mixture is heated under reflux for about 1-0 minutes and is concentrated by evaporation to a volume of 5 cc. 1 cc. of acetic acid is added thereto. The mixture is extracted with chloroform. The chloroform extracts. are washed with 2 N hydrochloric acid, water, and sodium bicarbonate solution, and again with water. They are dried over magnesium sulfate and are evaporated to dryness in a vacuum. The residue is dissolved in a mixture of 4 cc. of pyridine and 3 cc. of acetic acid anhydride. The reaction mixture is allowed to stand at 40 C. for 10 minutes and is evaporated to dryness in a vacuum. The residue is dissolved in a mixture of acetic acid ethyl ester and ether (2:3). The solution is cooled with ice. The resulting crystals are filtered off. 1.2 g. of 1813-acetoxy-l1,17a-dimeth0xy-3-oxo-lGit-methoxy carbonyl-2,3-seco-20a-yohimbane in the dextrorotatory form are obtained. Its melting points are 162 C. and 184 C. after intermediate resolidification. Its optical rotation is [a] =+31i2 (concentration: 0.5% in ethanol). The yield is 60% of the theoretical yield. This product is obtained in the form of colorless prismatic crystals which are soluble in acetone and chloroform and almost insoluble in ether.

Analysis (C H O N =472.52). Calculatedz 63.54%. C, 683% H, 23.70% 0, 5.93% N. Found: 63.8% C, 6.7% H, 23. 6% 0, 6.0% N. l

' (k) PREPARATION OF 1-8fi-HYDROXY-11,li'a-DIMETH OXY e 0X0 16B CARBOXY 2,3 SECO 20a Yo- 'HIMBANE (FORMULA VII) 4 g. of 18fi-acetoxy-11,17a-dimethoxy-3-oxo-l6fi-methoxy carbonyl-2,3-seco-20a-yohimbane of the melting point of 184 C. and the optical rotation [a] =+3l (concentration: 0.5 in ethanol), are dissolved in a mixture of 84 cc. of absolute methanol, 24 cc. of water, and 12 cc. of 10 N sodium hydroxide solution. The mixture is boiled underrefiux for about 1 hour, acidified by the addition of 10 N hydrochloric acid to a pH of 1.0, and concentrated by evaporation in a vacuum until it becomes) turbid. It is then cooled with ice. The resulting precipitate is: filtered ofi, washed with water, and dried. Thereby, 3.11 g. of compound VH are obtained in a yield of 89% of the theoretical yield. The compound is recrystallized from aqueous methanol. Its melting point is C. and its optical rotation is [a] =-"+34 (concentration: 0.5 in ethanol). The compound is only very slightly soluble in Water, but soluble in alkali hydroxide solution and in aqueous methanol.

Analysis (C H O N =416.46).-Oalculated: 63.44% C, 6.78% H, 23.05% 0, 6.73% N. Found: 63.3% C, 6.80% H, 23.4% 0, 6.8% N.

The same process may also be applied to the levorotatory 1813 acetoxy 11,170: dimethoxy 3 oxo 1618- methoxy carbonyl2,3-seco-20a-yohimbane. Thereby the 1 5 levorotatory yohimbane compound is also obtained. This compound of Formula VII can readily be converted into the enantiomorphous isomer of natural reserpine as will be described hereinafter. The process can, of course, also be applied to the racemic mixture of 1818-acetoxy-11, 17adimethoxy-3-oxo-16fl-meth0xy carbony1-2,3-seco20ayohimbane.

EXAMPLE 12 Preparation of the lactone-f J8/3-hydroxy-11,17a-dimethoxy 3 0x0 166 carboxy 2,3 seco-20a-y0himbane (Formula VIII) 3g. of the compound obtained according to the process described in Example 11k are heated with 30 cc. of acetic acid anhydride, 30 cc. of acetic acid, and 1.5 g. lithi um acetate in a stoppered containertor 2 hours. The mixture is allowed to cool, water is added thereto, and the resulting mixture is allowed to crystallize. The crystals are filtered off, washed with water, and dried. 1.57 g. of the lactone compound are obtained thereby. The mother liquors remaining after filtering 01f the crystals are extracted with methylene chloride. The extract is washed with sodium hydroxide solution and with water. The washed extract is dried over magnesium sulfate and evaporated to dryness. After recrystallization of the residue from aqueous acetone, 610 mg. of the lactone compound are recovered so that the total yield in this step is 76%. The lactone forms colorless crystals of the melting point 175 C. and the optical rotation (concentration: 0.25% in ethanol). The compound is soluble in chloroform, acetone, acetic acid ethyl ester, and is slightly soluble in alcohol.

Analysis (C H O N =398.44) .C-alcula'ted: 66.31% C, 6.58% H, 20.08% 0, 7.03% N. Found: 66.1% C, 6.7% H, 19.7% 0, 6.8% N.

The same process can be applied to the enantiomorphous isomer of the yohimbane compound of Formula VII whereby the corresponding dextrorotatory lactone of Formula VIII is obtained which melts at 175 C. and has an optical rotation [u] =+86 (concentration: 0.25 in ethanol). This compound also yields, as will be described hereinafter, the enantiornorphous isomer of natural reserpine.

The process can likewise be applied to the racem'ic yohirn'bane compound of Formula VII. I

'It is possible to eifect the lactonization described hereinabove in the absence of acetic acid.

- EXAMPLE 13 Preparation of the lactone of reserp'ic acid (Formula X) 2.6 g. of the levorotatory lactone of Formula VII obtained according to Example 12 are boiled under reflux with 90 cc. of phosphorus oxychloride for 2 hours. Excess phosphorus oxychloride is removed by distillation of the reaction mixture to dryness. The resulting residue which contains the quaternary base of the lactone of reserpic acid of Formula IX is dissolved in 180 cc. of acetic acid and the solution is heated under reflux after addition of 15 g. of zinc powder and cc. of water.

16 After boiling for 40 minutes, the mixture is cooled, zinc is filtered off and washed with acetone. The wash Waters are combined with the acetic acid filtrate and the combined wash waters and filtrate are evaporated to dryness. The residue is dissolved in chloroform. I- he chloroform extracts are washed first with water and :then' with ammonia and are dried over magnesium sulfate.

They are filtered and evaporated to dryness in a vacuum. After recrystallization from acetone 1.32 g. of the lactone of reserpic acid are obtained. The yield is 52%. The compound is identical with the compound obtained from natural reserpine and possesses the same characteristic properties as they are described in the literature.

When proceeding under the same reaction conditions and using the dextrorotatory enantiomorphous lactone compound of Formula VIII, the enantiomorphous lactone of reserpic acid is produced.

It is, of course, understood that the reduction can also be effected by means of an alkali met-a1 borohydr-ide. However, .such a reduction method yields the lactone of iso-reserpic acid which must be isomerized to the lactone of reserpic acid by a treatment with pivalic acid according to methods known per se.

We claim:

1. The process of producing the levorotatory lactone of Goa bronro 8B hydroxy 2a methoxy 33,513- epoxy '7 oxo 4am,8aa decahydronaphthalene- 1B- carboxylic acid comprising the steps of subjecting the levorotatory 1,8-lactone of v6m-ln'omo-7fi,8f3=dihydroxy-2ozmethoxy 35,5,8 epoxy 4aa,8aa decahydronaphthalene-lfi carboxylic acid to the action of chromic .acid in aqueous acetic acid in the presence of phosphoric acid and a water-immiscible lower alkyl halogenide at about room temperature, separating the organic layer and "recovering the levorotatory lactone of 6a-bromo-8B-hydroxy 2a methoxy 3fi,5fi epoxy 7 oxo 4au,8audecahydronaphthalene-lfi-carboxylic acid from said organic layer. a

2. The process according to claim 1, wherein the waterimmiscible lower alkyl halogenide is selected from the group consisting of dichloroethane, tetrachloroethane and methylene chloride.

3. The process according to claim 1, whereinrecovering said levorotatory lactone of Goc-bIOmO-Sfl-hYdIOXY- 20c methoxy 36,5;3 epoxy 7 oxo 4aa,8aadeca.'hydronaphthalene-lfi=carboxylic acid is effected by evaporating said organic layer to dryness, dissolving the'crude lactone in ethyl acetate and crystal-lizing the purified lactone therefrom.

References Cited in the file-of this patent UNITED STATES PATENTS MacPhillamy 'et a1. Apr. 9, 21957 Kuehne -Oct. 21, 1958 

1. THE PROCESS OF PRODUCING THE LEVOROTATORY LACTONE OF 6A-BROMO-8B-HYDROXY-2A-METHOXY-3B,5B,EPOXY-7-OXO4AA, 8AA-DECAHYDRONAPHTHALENE - 1B - CARBOXYLIC ACID COMPRISING THE STEPS OF SUBJECTING THE LEVOROTATORY 1,8-LACTONE OF 6A-BROMO - 7B,8B - DIHYDROXY-2A-METHOXY-3B,5B-EPOXY4AA,8AA-DECAHYDRONAPHTHALENE-1B-CARBOXYLIC ACID TO THE ACTION OF CHROMIC ACID IN AQUEOUS ACETIC ACID IN THE PRESENCE OF PHOSPHORIC ACID AND A WATER-IMMISCIBLE LOWER ALKYL HALOGENIDE AT ABOUT ROOM TEMPERATURE, SEPARATING THE ORGANIC LAYER AND RECOVERING THE LEVOROTATORY LACTONE OF 6A-BROMO-8B-HYDROXY-2A-METHOXY-3B,5B-EPOXY-7-OXO4AA,8AA-DECAHYDRONAPHTHALENE-1B-CARBOXYLIC ACID FROM SAID ORGANIC LAYER. 